| Structural highlights
6emk is a 10 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | NonStd Res: | |
| Gene: | TOR2, DRR2, TSC14, YKL203C (Baker's yeast), LST8, YNL006W, N2005 (Baker's yeast), AVO2, YMR068W, YM9916.07 (Baker's yeast), AVO1, YOL078W, O1110 (Baker's yeast) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[AVO2_YEAST] Component of TORC2, which regulates cell cycle-dependent polarization of the actin-cytoskeleton and cell wall integrity. TORC2 controls polarity of the actin cytoskeleton, which is required for orienting the secretory pathway toward discrete growth sites, via the RHO1/PKC1/MAPK cell integrity pathway. [TOR2_YEAST] Phosphatidylinositol 3-kinase homolog, component of both TORC1 and TORC2. TORC1 regulates multiple cellular processes to control cell growth in response to environmental signals. Nutrient limitation and environmental stress signals cause inactivation of TORC1. Active TORC1 positively controls ribosome biogenesis via control of rRNA, ribosomal protein and tRNA gene expression, and rRNA processing. TORC1 positively controls protein biosynthesis by regulation of mRNA stability, translation initiation factor activity, and high-affinity amino acid permeases that serve to provide amino acids for use by the translation machinery. TORC1 also promotes growth by sequestering a number of nutrient and general stress-responsive transcription factors in the cytoplasm. TORC1 negatively controls macroautophagy, a process to recycle surplus cytoplasmic mass under nutrient starvation conditions. TORC1 controls many of these processes via TIP41-TAP42-mediated inhibition of the type 2A-related phosphatases PP2A and SIT4 (PubMed:10198052, PubMed:10329624, PubMed:10604478, PubMed:11741537, PubMed:15620355, PubMed:7606777, PubMed:8741837, PubMed:9539725, PubMed:9843498). In nutrient rich conditions, responsible for the phosphorylation of AGC S6 kinase (S6K) YPK3, activating YPK3 kinase activity and promoting phosphorylation of ribosomal protein S6 (PubMed:25767889). Phosphorylates kinase SCH9 at 6 amino acids in the C-terminus, activating SCH9 kinase activity to properly regulate ribosome biogenesis, translation initiation, and entry into stationary phase (PubMed:17560372). TORC2 regulates cell cycle-dependent polarization of the actin-cytoskeleton, cell wall integrity, and receptor endocytosis. TORC2 controls polarity of the actin cytoskeleton, which is required for orienting the secretory pathway toward discrete growth sites, via the RHO1/PKC1/MAPK cell integrity pathway by activating the RHO1 guanine nucleotide exchange factor ROM2. TORC2 phosphorylates the AGC kinase YPK2, an upstream effector of the cell integrity pathway. TORC2 negatively regulates calcineurin-dependent stress signaling via phosphorylation of its effector SLM1-SLM2 (PubMed:14593073, PubMed:15372071, PubMed:16055732, PubMed:16959779, PubMed:8846782, PubMed:8943012).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [LST8_YEAST] Essential component of both TORC1 and TORC2. TORC1 regulates multiple cellular processes to control cell growth in response to environmental signals. Nutrient limitation and environmental stress signals cause inactivation of TORC1. Active TORC1 positively controls ribosome biogenesis via control of rRNA, ribosomal protein and tRNA gene expression, and rRNA processing. TORC1 positively controls protein biosynthesis by regulation of mRNA stability, translation initiation factor activity, and high-affinity amino acid permeases that serve to provide amino acids for use by the translation machinery. TORC1 also promotes growth by sequestering a number of nutrient and general stress-responsive transcription factors in the cytoplasm. TORC1 negatively controls macroautophagy, a process to recycle surplus cytoplasmic mass under nutrient starvation conditions. LST8 is involved in the negative regulation of transcription factors GLN3 and RTG1-RTG3, limiting the synthesis of alpha-ketoglutarate, glutamate and glutamine. LST8 is required for targeting of amino acid permeases (AAPs) to the plasma membrane. TORC2 regulates cell cycle-dependent polarization of the actin-cytoskeleton, cell wall integrity, and receptor endocytosis. TORC2 controls polarity of the actin cytoskeleton, which is required for orienting the secretory pathway toward discrete growth sites, via the RHO1/PKC1/MAPK cell integrity pathway. LST8 is involved in maintenance of cell wall integrity. LST8 modulates TOR2 kinase activity.[18] [19] [20] [AVO1_YEAST] Component of TORC2, which regulates cell cycle-dependent polarization of the actin-cytoskeleton and cell wall integrity. TORC2 controls polarity of the actin cytoskeleton, which is required for orienting the secretory pathway toward discrete growth sites, via the RHO1/PKC1/MAPK cell integrity pathway.
Publication Abstract from PubMed
The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Avo3/Rictor is unique to TORC2, but interacts with the same HEAT repeats of Tor2 that are engaged by Kog1/Raptor in mammalian TORC1, explaining the mutual exclusivity of these two proteins. Density, which we conclude is Avo3, occludes the FKBP12-rapamycin-binding site of Tor2's FRB domain rendering TORC2 rapamycin insensitive and recessing the kinase active site. Although mobile, Avo1/hSin1 further restricts access to the active site as its conserved-region-in-the-middle (CRIM) domain is positioned along an edge of the TORC2 active-site-cleft, consistent with a role for CRIM in substrate recruitment.
Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2.,Karuppasamy M, Kusmider B, Oliveira TM, Gaubitz C, Prouteau M, Loewith R, Schaffitzel C Nat Commun. 2017 Nov 23;8(1):1729. doi: 10.1038/s41467-017-01862-0. PMID:29170376[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Powers T, Walter P. Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell. 1999 Apr;10(4):987-1000. PMID:10198052
- ↑ Jiang Y, Broach JR. Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J. 1999 May 17;18(10):2782-92. PMID:10329624 doi:http://dx.doi.org/10.1093/emboj/18.10.2782
- ↑ Beck T, Hall MN. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature. 1999 Dec 9;402(6762):689-92. PMID:10604478 doi:http://dx.doi.org/10.1038/45287
- ↑ Jacinto E, Guo B, Arndt KT, Schmelzle T, Hall MN. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol Cell. 2001 Nov;8(5):1017-26. PMID:11741537
- ↑ deHart AK, Schnell JD, Allen DA, Tsai JY, Hicke L. Receptor internalization in yeast requires the Tor2-Rho1 signaling pathway. Mol Biol Cell. 2003 Nov;14(11):4676-84. PMID:14593073 doi:http://dx.doi.org/10.1091/mbc.E03-05-0323
- ↑ Audhya A, Loewith R, Parsons AB, Gao L, Tabuchi M, Zhou H, Boone C, Hall MN, Emr SD. Genome-wide lethality screen identifies new PI4,5P2 effectors that regulate the actin cytoskeleton. EMBO J. 2004 Oct 1;23(19):3747-57. Epub 2004 Sep 16. PMID:15372071 doi:10.1038/sj.emboj.7600384
- ↑ Martin DE, Soulard A, Hall MN. TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1. Cell. 2004 Dec 29;119(7):969-79. PMID:15620355 doi:http://dx.doi.org/S0092867404011511
- ↑ Kamada Y, Fujioka Y, Suzuki NN, Inagaki F, Wullschleger S, Loewith R, Hall MN, Ohsumi Y. Tor2 directly phosphorylates the AGC kinase Ypk2 to regulate actin polarization. Mol Cell Biol. 2005 Aug;25(16):7239-48. PMID:16055732 doi:http://dx.doi.org/25/16/7239
- ↑ Mulet JM, Martin DE, Loewith R, Hall MN. Mutual antagonism of target of rapamycin and calcineurin signaling. J Biol Chem. 2006 Nov 3;281(44):33000-7. Epub 2006 Sep 7. PMID:16959779 doi:M604244200
- ↑ Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell. 2007 Jun 8;26(5):663-74. doi: 10.1016/j.molcel.2007.04.020. PMID:17560372 doi:http://dx.doi.org/10.1016/j.molcel.2007.04.020
- ↑ Gonzalez A, Shimobayashi M, Eisenberg T, Merle DA, Pendl T, Hall MN, Moustafa T. TORC1 promotes phosphorylation of ribosomal protein S6 via the AGC kinase Ypk3 in Saccharomyces cerevisiae. PLoS One. 2015 Mar 13;10(3):e0120250. doi: 10.1371/journal.pone.0120250., eCollection 2015. PMID:25767889 doi:http://dx.doi.org/10.1371/journal.pone.0120250
- ↑ Zheng XF, Florentino D, Chen J, Crabtree GR, Schreiber SL. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell. 1995 Jul 14;82(1):121-30. PMID:7606777
- ↑ Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996 Jan;7(1):25-42. PMID:8741837
- ↑ Cardenas ME, Heitman J. FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. EMBO J. 1995 Dec 1;14(23):5892-907. PMID:8846782
- ↑ Schmidt A, Kunz J, Hall MN. TOR2 is required for organization of the actin cytoskeleton in yeast. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13780-5. PMID:8943012
- ↑ Berset C, Trachsel H, Altmann M. The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4264-9. PMID:9539725
- ↑ Schmidt A, Beck T, Koller A, Kunz J, Hall MN. The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J. 1998 Dec 1;17(23):6924-31. PMID:9843498 doi:http://dx.doi.org/10.1093/emboj/17.23.6924
- ↑ Liu Z, Sekito T, Epstein CB, Butow RA. RTG-dependent mitochondria to nucleus signaling is negatively regulated by the seven WD-repeat protein Lst8p. EMBO J. 2001 Dec 17;20(24):7209-19. PMID:11742997 doi:http://dx.doi.org/10.1093/emboj/20.24.7209
- ↑ Chen EJ, Kaiser CA. LST8 negatively regulates amino acid biosynthesis as a component of the TOR pathway. J Cell Biol. 2003 Apr 28;161(2):333-47. doi: 10.1083/jcb.200210141. PMID:12719473 doi:http://dx.doi.org/10.1083/jcb.200210141
- ↑ Roberg KJ, Bickel S, Rowley N, Kaiser CA. Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8. Genetics. 1997 Dec;147(4):1569-84. PMID:9409822
- ↑ Karuppasamy M, Kusmider B, Oliveira TM, Gaubitz C, Prouteau M, Loewith R, Schaffitzel C. Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2. Nat Commun. 2017 Nov 23;8(1):1729. doi: 10.1038/s41467-017-01862-0. PMID:29170376 doi:http://dx.doi.org/10.1038/s41467-017-01862-0
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